Patients with B cell lymphoma usually require treatment with a combination of several cytotoxic chemotherapy agents to control their disease and usually need more than one course of treatment. Recently, the successful use of non-toxic monoclonal anti-CD20 antibody, rituximab, to treat B cell lymphoma has produced a great deal of excitement and new hope. However, the response rate is relatively low compared to chemotherapy and antibody treatment alone does not appear to be curative. If we can understand how monoclonal antibodies mediate their anti-tumor effect, it is possible to increase their efficacy by developing new ways to use them and design more effective antibodies based on what we learn. The hypothesis tested in this project is that monoclonal antibodies such as rituximab mediate their anti-lymphoma activity either by antibody-mediated killing and a direct anti-tumor effect on tumor cells. I plan to test this hypothesis through a systematic analysis of these mechanisms on primary tumor samples from rituximab-treated patients. Recently, we have shown evidence that antibody-dependent cellular cytotoxicity (ADCC) plays a major role in rituximab's anti-tumor effect. The specific aims of this project are designed to extend our previous finding: [unreadable] [unreadable] 1) To dissect the mechanism of antibody-mediated cytotoxicity induced by rituximab. [unreadable] 2) To analyze the direct effect of rituximab on lymphoma cells. [unreadable] 3) To characterize anti-CD20 variants with altered Fc that bind Fc receptor with higher affinity. [unreadable] 4) To define the mechanism of rituximab resistance. [unreadable] [unreadable] By this systematic analysis of primary tumor cells from rituximab-treated patients, we have a unique opportunity to learn how rituximab works in patients, and how treatment resistance develops. The knowledge generated from this project will help us to design better ways to use monoclonal antibodies and to develop new reagents to treat patients with B cell lymphoma. [unreadable] [unreadable]